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Biotin Carboxylase: The Key Enzyme in Cellular Metabolism and Its Clinical Significance

When you search for “biotin carboxylase,” you are likely seeking clear, authoritative answers about this specific enzyme. Your needs generally fall into several key areas: a basic definition and English terminology, its crucial biological functions, associated genetic disorders, related enzymes and proteins, and its research and clinical significance. This article will comprehensively address these points.

1. What is Biotin Carboxylase? Clarifying the Basic Definition and English Terminology

Biotin Carboxylase (BC) is a critical component of multi-enzyme complexes that depend on the vitamin biotin. Its name precisely describes its function:

• Biotin: A water-soluble vitamin (Vitamin B7 or Vitamin H) that acts as a coenzyme.
• Carboxylase: An enzyme that catalyzes the incorporation of a carboxyl group (-COOH) into a substrate.

Therefore, Biotin Carboxylase is the enzyme responsible for the first half of the carboxylation reaction: it activates CO₂ and transfers it to the biotin cofactor that is covalently attached to another protein.

It’s important to distinguish it from other biotin-dependent enzymes. Biotin carboxylase is one part of larger complexes, the most famous of which is Acetyl-CoA Carboxylase (ACC).

• Acetyl-CoA Carboxylase (ACC): This enzyme carboxylates acetyl-CoA to form malonyl-CoA, the first and rate-limiting step in fatty acid synthesis. ACC is a multi-subunit complex in bacteria and plants, and in mammals, it is a multi-domain protein. The biotin carboxylase domain is one of these key parts.

2. Core Biological Function: What Does Biotin Carboxylase Do?

The function of biotin carboxylase is fundamental to life. It executes the first step in a two-step carboxylation process:

1. Activation of CO₂: Biotin carboxylase uses ATP to “activate” a molecule of bicarbonate (HCO₃⁻), converting it into a highly reactive carboxyphosphate intermediate.
2. Carboxylation of Biotin: This activated CO₂ is then transferred to the nitrogen atom on the biotin cofactor that is bound to a biotin carboxyl carrier protein (BCCP), forming carboxybiotin.

The subsequent step is carried out by carboxyltransferase, which transfers the carboxyl group from carboxybiotin to the target substrate (e.g., acetyl-CoA to make malonyl-CoA).

This mechanism is essential in two major metabolic pathways:

• Fatty Acid Synthesis: As part of ACC, it produces malonyl-CoA, the essential building block for making long-chain fatty acids.
• Gluconeogenesis: As part of Pyruvate Carboxylase (PC), it helps convert pyruvate to oxaloacetate, a crucial step for the liver to produce new glucose.

3. Association with Genetic Diseases: Biotin Carboxylase Deficiency

Mutations in the genes encoding biotin carboxylase can lead to a rare but serious autosomal recessive metabolic disorder. It is one of the four core deficiencies classified under Multiple Carboxylase Deficiency.

• Cause: The defect is specifically in the BCKDHB gene, which encodes the biotin carboxylase subunit of the propionyl-CoA carboxylase (PCC) enzyme.
• Consequence: This disrupts the breakdown of several specific amino acids (isoleucine, valine, threonine, methionine), odd-chain fatty acids, and cholesterol. This leads to a dangerous accumulation of toxic organic acids (like 3-hydroxypropionic acid and methylcitric acid) in the blood and urine.
• Symptoms: Typically appearing in infancy, symptoms can be life-threatening and include severe metabolic acidosis, ketosis, lethargy, vomiting, hypotonia (low muscle tone), developmental delay, and rash.
• Treatment: The condition is often manageable with a tailored diet low in the precursor amino acids, carnitine supplementation, and in some cases, strict metabolic monitoring.

4. Related Enzymes and Proteins: Building a Complete Picture

To fully understand biotin carboxylase, it’s helpful to know its partners in the process:

• Biotin Carboxyl Carrier Protein (BCCP): This protein is covalently attached to the biotin cofactor. It acts as a “swinging arm,” shuttling the activated CO₂ from the biotin carboxylase active site to the carboxyltransferase active site.
• Carboxyltransferase: This is the second catalytic component that completes the reaction by transferring the carboxyl group from carboxybiotin to the final substrate.
• Propionyl-CoA Carboxylase (PCC) & Pyruvate Carboxylase (PC): These are other crucial biotin-dependent enzymes that contain a biotin carboxylase domain/subunit. PCC is involved in amino acid metabolism, while PC bridges glycolysis and the citric acid cycle.

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5. Research and Clinical Significance

Biotin carboxylase is a significant target in various fields of research:

• Drug Discovery for Obesity and Diabetes: Since ACC1 (the isoform in the cytosol) controls fatty acid synthesis, and ACC2 (the mitochondrial isoform) controls fatty acid oxidation, inhibiting ACC is a promising strategy for treating metabolic syndrome. Developing specific inhibitors for the biotin carboxylase domain is an active area of pharmaceutical research.

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• Antibiotic Development: The bacterial ACC enzyme is structurally different from the human version, making it a potential target for new antibiotics that would not harm human cells.
• Agricultural Applications: Understanding and engineering biotin carboxylase in plants could lead to crops with altered oil content or improved stress resistance.

Conclusion